19-11133059-C-T

Variant names:

• chr19-11133059-C-T
• rs2738467
• NM_000527.5:c.*1743C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000527.5(LDLR):​c.*1743C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 151,446 control chromosomes in the GnomAD database, including 10,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (10219 hom., cov: 30)
  • Exomes 𝑓: 0.54 (4 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.84
• Publications: 17 publications found

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

SPC24 (HGNC:26913): (SPC24 component of NDC80 kinetochore complex) Predicted to be involved in cell division. Located in nucleolus and nucleoplasm. Part of Ndc80 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-11133059-C-T is Benign according to our data. Variant chr19-11133059-C-T is described in ClinVar as Benign. ClinVar VariationId is 328106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.*1743C>T		3_prime_UTR	Exon 18 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.*1743C>T		3_prime_UTR	Exon 18 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.*1743C>T		3_prime_UTR	Exon 17 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.*1743C>T		3_prime_UTR	Exon 18 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.*1743C>T		3_prime_UTR	Exon 18 of 18	ENSP00000252444.6
	LDLR	ENST00000559340.2	TSL:5	n.*2395C>T		non_coding_transcript_exon	Exon 17 of 17	ENSP00000453696.2

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50200 AN: 151302 Hom.: 10228 Cov.: 30

Gnomad AFR AF: 0.0876

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.426

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.368

GnomAD4 exome AF: 0.542 AC: 13 AN: 24 Hom.: 4 Cov.: 0 AF XY: 0.438 AC XY: 7 AN XY: 16

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.611 AC: 11 AN: 18

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.331 AC: 50187 AN: 151422 Hom.: 10219 Cov.: 30 AF XY: 0.336 AC XY: 24834 AN XY: 73938

African (AFR) AF: 0.0875 AC: 3613 AN: 41286

American (AMR) AF: 0.426 AC: 6460 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1332 AN: 3464

East Asian (EAS) AF: 0.191 AC: 975 AN: 5118

South Asian (SAS) AF: 0.374 AC: 1796 AN: 4802

European-Finnish (FIN) AF: 0.499 AC: 5216 AN: 10454

Middle Eastern (MID) AF: 0.414 AC: 120 AN: 290

European-Non Finnish (NFE) AF: 0.437 AC: 29625 AN: 67840

Other (OTH) AF: 0.367 AC: 770 AN: 2100

Alfa AF: 0.338 Hom.: 3211

Bravo AF: 0.314

Asia WGS AF: 0.258 AC: 896 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.099
DANN	Benign	0.47
PhyloP100		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2738467; hg19: chr19-11243735;